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The Mesothelioma Applied Research Foundation's team of experts is available to answer your questions about mesothelioma, its symptoms and treatments as well as options available to you. This help is a free service. We are not a law firm. Read more about the Mesothelioma Applied Research Foundation.

TO GET HELP CALL: (877) End-Meso or (877) 363-6376 or fill out the form to the right to be contacted by us.

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DoD Mesothelioma Research Funding Information

Significant Funding Opportunity for Mesothelioma Investigators
DOD Peer Reviewed Cancer Research Program

The Mesothelioma Applied Research Foundation (Meso Foundation) is pleased to provide background information for investigators interested in pursuing research funding under the Department of Defense (DOD) Peer Reviewed Cancer Research Program (PRCRP) in FY 2013.

You can view a detailed program announcement, application instructions and submission deadlines at
http://cdmrp.army.mil/funding/prcrp.shtml

A top priority for the Meso Foundation has been to strengthen the federal government’s response to the mesothelioma tragedy through a commitment of new federal research dollars. Our advocacy efforts finally paid off when in 2008, for the first time, mesothelioma was included as a research priority within the DOD PRMRP. Through the 2008 and 2009 grant cycles five mesothelioma researchers were successful in obtaining funding through the PRMRP program. This year mesothelioma is being included in the Peer Reviewed Cancer Research Program (PRCRP).

This funding opportunity can serve as a vital resource to help advance the research and treatment of mesothelioma. The Meso Foundation strongly encourages mesothelioma investigators to consider submitting applications for funding. The interest and engagement shown by the mesothelioma research community will likely be a factor in whether mesothelioma is included as an eligible subject in future years. Therefore please let us know of your intention of applying by emailing Melinda Kotzian at mkotzian@curemeso.org so that we can continue to advocate effectively for medical research funding for mesothelioma.

Tips for Demonstrating Military Relevance

A complete search of previously funded research can be found at the website for the DOD PRMRP at http://cdmrp.army.mil/search.aspx. The Meso Foundation can also provide summaries and technical abstracts of interest to mesothelioma investigators applying for funds under this program.

While we strongly encourage investigators to make as strong of a military connection as possible, establishing acceptable levels of military relevance can be done relatively easily and creatively. You might consider the following suggestions:

•Reference the established history of asbestos exposure in military service, and elevated risk of mesothelioma in the military population. In one large study, Navy or shipyard exposures totaled one third of mesothelioma cases. (Butnor, Sharma, Sporn, Roggli: Malignant mesothelioma and occupational exposure to asbestos: an analysis of 1445 cases. Ann Occup Hyg 2002; 46: 150-153.)

•Reinforce that the military and veteran populations are at higher risk of developing mesothelioma due to service related exposures to asbestos. Given the long latency of the disease, even if exposures are reduced, mesothelioma will continue to affect the veteran and military population for decades to come.

•Collaborate and integrate your project with military and/or Veterans Affairs (VA) research laboratories and hospitals. Please note that it is strongly encouraged that you include letters of support and verification letter(s) if your submission includes the involvement of military recruits or subjects, military-controlled study materials, databases, and/or restricted facilities.

If you need additional information on criteria for demonstrating military relevance, please contact the Meso Foundation directly at 703-879-3825.

Details on the Past PRMRP Funded Mesothelioma Projects

2008 Grant Cycle

V. Courtney Broaddus – University of California, San Francisco – Investigator Initiated Research Award
Award Amount: $1,363,465.00

Background: Mesothelioma, an incurable and chemoresistant tumor induced by asbestos, is in part characterized by a robust immune response involving infiltration of neoplastic tissue by macrophages. Macrophages are now recognized as possessing dual immuno-modulatory roles in tumors where some activities may hinder tumor growth, whereas others may bolster and induce cancer development. In preliminary studies, we have revealed that the chemo-resistance of mesotheliomas to pharmacologic agents that typically induce apoptosis can be regulated by the presence of macrophages within tumors.

Objective/Hypothesis: We have revealed that within human mesotheliomas exists a large population of immune cells, i.e., macrophages, that regulate sensitivity of mesothelioma cells to cytotoxic anticancer agents. Recent data indicate that macrophages can be targeted therapeutically to undermine some aspects of cancer development. Thus, the overall objective of the project is to determine the functional significance of macrophages as regulators of chemosensitivity of human mesotheliomas, and to design therapeutic strategies to target macrophages to enhance chemosensitivity of human mesothelioma to minimize tumor burden and disease progression. To accomplish our objective, we propose (i) To determine the functional significance of the macrophage phenotype in mesothelioma, (ii) To determine the functional significance of macrophages as regulators of mesothelioma apoptosis in vitro, and (iii) To define functional significance of macrophage depletion or repolarization on mesothelioma survival in vivo. For these aims, we will use a combination of state-of-the-art ex vivo organotypic co-culture models, an in vivo model of murine mesothelioma, and routine availability of freshly resected human mesothelioma tissue.

Impact: Our laboratories have combined their expertise and interest to address a novel approach to mesothelioma therapy, namely, to define the functional significance and to manipulate one of the major cell populations within mesothelial tumors, namely, the tumor-associated macrophage. Our preliminary data indicate that macrophage function can be altered by cytokine exposure and thereby enhance mesothelioma cell apoptotic responses to cytotoxic therapy. Thus, the potential of these studies lies in the possibility of revealing macrophage effector functions that can be re-directed as potent antitumor tools.

2009 Grant Cycle

Joseph Testa, MD - Fox Chase Cancer Center - Idea Award
Award Amount: $657,517.00

Background: According to the U.S. Department of Veterans Affairs, >30% of Americans with malignant mesothelioma (MM) were exposed to asbestos during military service. The U.S. Department of Defense recognizes MM as a service-related disease due the widespread use of asbestos in naval shipyards from the 1930s through the 1980s. Military personnel who were stationed on ships or worked at shipyards during this time period hold a greater risk of developing asbestos-related diseases such as MM. Patients with MM usually present with advanced stage disease that is often surgically inoperable and refractory to standard chemotherapies. Epidemiological studies have established that exposure to asbestos fibers is the primary cause of MM. In addition to causing mesothelioma, exposure to asbestos causes conditions such as fibrosis of the lung and asbestosis, both inflammatory diseases. Over a century ago, a link between cancer and inflammation was demonstrated and has been extensively studied in various human cancers. Cancer-related inflammation (CRI) is normally confined to the tumor microenvironment and can contribute to tissue remodeling, angiogenesis, and metastasis. As a result, studies have demonstrated the requirement of inflammation for the pathogenesis and progression of many human cancers. Exposure to asbestos causes inflammation through a cellular complex called the NALP3-inflammasome, which induces the release of IL-1beta, a known stimulant of mesothelial cell proliferation. Although recent studies have demonstrated that NALP3 inflammasome-deficient mice do not develop a productive inflammatory response to asbestos, the requirement of inflammasome-mediated inflammation in the development of asbestos-induced MM has not been formally tested.

Objective/Hypothesis: Asbestos exposure causes inflammation through the NALP3 inflammasome. The role of CRI in MM pathogenesis and progression has not been formally tested to date. Asc is one of three proteins making up the NALP3 inflammasome, and we hypothesize that mice deficient for Asc would be less prone to the induction of MM by asbestos.

Specific Aims:

1) Directly determine, using a genetically-defined mouse model, if NALP3 inflammasome-mediated inflammation is required for the induction of MM by asbestos.

2) Ascertain if NALP3 inflammasome-mediated IL-1beta signaling is required for asbestos-induced MM tumorigenesis, using an IL-1R antagonist.

Study Design: For Aim 1, we will use Asc (+/-) and (-/-) mice and directly compare them to wild-type mice for MM induction by asbestos for relative differences in tumor incidence and latency. This work will test whether NALP3 inflammasome-mediated inflammation is required for MM development in vivo. We will also evaluate whether macrophage infiltration and IL-1beta levels are altered in mesothelial tissues of Asc (+/-) and (-/-) mice, compared to wild-type mice, when animals are exposed to asbestos. In Aim 2, tumor incidence and latency will be evaluated in Nf2;Cdkn2a/Arf (+/-) mice exposed to asbestos in the presence or absence of an IL-1R antagonist to determine if IL-1beta signaling is required for MM development in vivo. This work will provide insights regarding the possibility of preventing or delaying tumor formation using an inhibitor of a key step in the inflammatory response.

Impact: We propose that these investigations will formally evaluate whether asbestos-induced inflammation, through NALP3-inflammasome activation and IL-1beta release, is required for the development of MM. The results of these investigations will also further implicate a key role for inflammation in the pathogenesis of cancer generally, and open new avenues for prevention.

Innovation: The proposed project represents the first study that directly addresses, both genetically and pharmacologically, the requirement of asbestos-induced inflammation in the pathogenesis of MM. The studies outlined in this Idea Award proposal represent innovative approaches to address the requirement for inflammation in mouse models of asbestos-induced MM.

Lee Krug, MD - Memorial Sloan Kettering – Clinical Trial Award
Award Amount: $1,487,973.00

Background: Malignant pleural mesothelioma (MPM) is an uncommon cancer afflicting 3,000 patients annually in the U.S. The pathogenesis is linked to asbestos exposure, and shipworkers, such as Navy seamen, are at increased risk. MPM typically presents with a rind of tumor confined to the pleura. Fit patients diagnosed with stage I-III MPM may be considered for multimodality therapy including chemotherapy, surgical resection by pleurectomy/decortication or extrapleural pneumonectomy, and radiation. Despite this aggressive approach, however, patients typically relapse quickly and survival remains poor.

The Wilms' tumor gene, WT1, encodes transcription factors that regulate cell proliferation, differentiation, and apoptosis. Such a high percentage of mesothelioma tumors demonstrate WT1 expression that immunohistochemical staining for WT1 has become a routine diagnostic test. WT1 is a nuclear protein, but it is processed and presented on the tumor cell surface. This finding, along with the lack of expression in normal tissues, supports its use as a target of immunotherapy in MPM. WT1 as a self antigen is poorly immunogenic so various strategies are required to overcome tolerance. Using computer-based algorithms, WT1-based peptides were designed that bind with stronger affinities to HLA class I and class II molecules via the introduction of amino acid point mutations into certain MHC anchor motifs. The higher affinity "heteroclitic" peptides effectively stimulate T cells that can recognize native WT1 peptide sequences and can destroy mesothelioma tumor cells in vitro. MSKCC holds the IND for this vaccine. We conducted a pilot trial to determine the immunogenicity and safety of vaccination with our WT1 heteroclitic peptides in humans. In order to broaden the immune response in the setting of varied HLA subtypes, four different peptides are included in the vaccine. Peptides are suspended in Montanide adjuvant, and GM-CSF is administered at the injection site. Nine patients with mesothelioma and three patients with NSCLC were enrolled (nine in total are evaluable for immune response). Six patients showed increased proliferation to the immunizing peptides. Four patients responded to peptide 331, four patients responded to 427, and five patients responded to 122A1. Five out of seven HLA-A0201 positive patients were tested for CD8 T cell response to HLA-A0201-restricted peptide WT1-A by IFN-gamma ELISPOT assay. All five showed a significant increase in the numbers of IFN-gamma-secreting cells and the frequency of WT1-A/HLA-A0201 tetramer-positive CD8 T cells. One patient with recurrent MPM has no signs of disease progression 12 months after completion of the vaccinations. We have chosen to test the efficacy of this vaccine in MPM patients who have minimal disease burden after completion of multimodality therapy but who remain at exceedingly high risk for recurrence.

Objective/Hypothesis: Enhancing the cellular immune response to WT-1 through the administration of a WT-1 analog peptide vaccine will control residual disease in patients who have completed multimodality therapy for MPM.

Specific Aim: To conduct a randomized phase II trial of the WT1 peptide vaccine in patients with MPM as adjuvant therapy after completion of multimodality therapy.

Study Design: This is a multicenter, non-blinded, randomized trial comparing treatment with the WT-1 analog peptide vaccine + GM-CSF to nonspecific immunotherapy with GM-CSF alone in patients with MPM who have completed multimodality therapy. The primary endpoint is progression-free survival (PFS). The expected PFS is 12 months; an improvement to 18 months would be of interest. With a type I error of 20% and a power of 80%, enrollment period of 3 years, and follow-up of 2 years, the sample size required would be 90 patients (45 in each arm).

Impact: Should this vaccine demonstrate efficacy, it will provide a novel, nontoxic therapy that will improve the survival for thousands of patients with this devastating disease.

Harvey Pass, MD – NYU School of Medicine – Investigator Initiated Research Award
Award Amount: $684,396.00

Malignant Mesothelioma (MM) is a lethal cancer associated with exposure to asbestos. Poor median survival, resistance to chemo- and radio-therapies, and a delayed onset of the disease (10-20 years after exposure) demand the development of novel approaches providing more efficient diagnostic, prognostic, and therapeutic tools. Aberrant glycans on cell surfaces and in the circulation are found in 100% of cancers evaluated and aberrant glycosylation during malignant transformation is recognized as a potential target for biomarker translational research. Most tumor-associated carbohydrate antigens (TACAs) correlate with tumor progression, and the immune response in cancers is predominantly related to the carbohydrate moiety. Antiglycan antibodies (AGAs) can be detected using a printed glycan array (PGA), and our laboratory is the first and only site that is using PGA in translational research. Our PGA is composed of hundreds of glycans, most of which are present on normal, pathogen-infected cells and cancer cells, stimulated immune cells, and on human infectious agents. Our preliminary data show that human AGAs are far more abundant then previously assumed, and they can be easily profiled in a few microliters of serum in order to provide accurate and sensitive malignancy-diagnostic information.

True breakthroughs in anti-cancer treatments have been achieved using antibodies that target molecular patterns primarily found on cancer cells. Each of the therapeutic antibodies currently available, such as Herceptin and Avastin, targets one specific antigen that is present at high levels in many -- but not all -- tumor cells in tissues of cancer patients. Successful results already obtained with single-target antibody treatment strongly suggest that multiple therapeutic antibodies administered simultaneously would bring even greater anticancer and preventive activity. Yet, the key challenge is discovering the most appropriate targets for antibody therapeutics.

We hypothesize that the PGA can (1) define specific profiles distinguishing asbestos-exposed individuals from MM, (2) stratify MMs by good/bad prognosis, and (3) pinpoint immune dysregulation which may be ameliorated with the use of specific, TACA-targeting immunoglobulins.

The proposed study addresses our hypothesis with three specific aims. Specific Aim 1 will attempt to validate preliminary data from our laboratory that non-cancer bearing asbestos-exposed cohorts have distinct AGA profiles from patients with established MM, and that AGA profiles will be able to segregate MM patients by time to progression and overall survival. Specific Aim 2 will define temporal changes in serum AGAs using the PGA in order to profile glycan-associated mesothelial carcinogenesis and MM progression using a well established rat model of asbestos-induced MM. Specific Aim 3 will build on Specific Aim 2 by investigating the therapeutic implications of a PGA-guided cocktail of therapeutic antibodies against these multiple cancer cell surface targets as adjuvants to current efficacious MM chemotherapeutic strategies in our rat model. The uniqueness of this project rests not only with the first clinical PGA platform and glycan library applications, but also with the matching informatic analyses which allow for state of the art data interpretation and integration. It is hoped that the successful completion of this project could eventually lead to the development of a serum test for the preventive screening of US Armed Forces personnel and civilians known or suspected of asbestos exposure and generate "one of a kind proof-of-concept results" that may lead to major improvements in current therapeutic strategies used in MM, in this case by the development of most favorable scenarios for future human protocols investigating the simultaneous application of multiple syngeneic anti-TACA antibodies with selected combination treatment modalities.

Margaret Huflejt, PhD – NYU School of Medicine – Investigator Initiated Research Award
Award Amount: $578,180.00

Malignant Mesothelioma (MM) is a lethal cancer associated with exposure to asbestos. Poor median survival, resistance to chemo- and radio-therapies, and a delayed onset of the disease (10-20 years after exposure) demand the development of novel approaches providing more efficient diagnostic, prognostic, and therapeutic tools. Aberrant glycans on cell surfaces and in the circulation are found in 100% of cancers evaluated and aberrant glycosylation during malignant transformation is recognized as a potential target for biomarker translational research. Most tumor-associated carbohydrate antigens (TACAs) correlate with tumor progression, and the immune response in cancers is predominantly related to the carbohydrate moiety. Antiglycan antibodies (AGAs) can be detected using a printed glycan array (PGA), and our laboratory is the first and only site that is using PGA in translational research. Our PGA is composed of hundreds of glycans, most of which are present on normal, pathogen-infected cells and cancer cells, stimulated immune cells, and on human infectious agents. Our preliminary data show that human AGAs are far more abundant then previously assumed, and they can be easily profiled in a few microliters of serum in order to provide accurate and sensitive malignancy-diagnostic information.

True breakthroughs in anti-cancer treatments have been achieved using antibodies that target molecular patterns primarily found on cancer cells. Each of the therapeutic antibodies currently available, such as Herceptin and Avastin, targets one specific antigen that is present at high levels in many -- but not all -- tumor cells in tissues of cancer patients. Successful results already obtained with single-target antibody treatment strongly suggest that multiple therapeutic antibodies administered simultaneously would bring even greater anticancer and preventive activity. Yet, the key challenge is discovering the most appropriate targets for antibody therapeutics.

We hypothesize that the PGA can (1) define specific profiles distinguishing asbestos-exposed individuals from MM, (2) stratify MMs by good/bad prognosis, and (3) pinpoint immune dysregulation which may be ameliorated with the use of specific, TACA-targeting immunoglobulins.

The proposed study addresses our hypothesis with three specific aims. Specific Aim 1 will attempt to validate preliminary data from our laboratory that non-cancer bearing asbestos-exposed cohorts have distinct AGA profiles from patients with established MM, and that AGA profiles will be able to segregate MM patients by time to progression and overall survival. Specific Aim 2 will define temporal changes in serum AGAs using the PGA in order to profile glycan-associated mesothelial carcinogenesis and MM progression using a well established rat model of asbestos-induced MM. Specific Aim 3 will build on Specific Aim 2 by investigating the therapeutic implications of a PGA-guided cocktail of therapeutic antibodies against these multiple cancer cell surface targets as adjuvants to current efficacious MM chemotherapeutic strategies in our rat model. The uniqueness of this project rests not only with the first clinical PGA platform and glycan library applications, but also with the matching informatic analyses which allow for state of the art data interpretation and integration. It is hoped that the successful completion of this project could eventually lead to the development of a serum test for the preventive screening of US Armed Forces personnel and civilians known or suspected of asbestos exposure and generate "one of a kind proof-of-concept results" that may lead to major improvements in current therapeutic strategies used in MM, in this case by the development of most favorable scenarios for future human protocols investigating the simultaneous application of multiple syngeneic anti-TACA antibodies with selected combination treatment modalities.

DoD Archives 2009, 2008